---------------------DOSAGE FORMS AND STRENGTHS----------------------
`• 50 mg, 100 mg, 150 mg, 200 mg tablets (3)
`• 200 mg/20 mL single-dose vial for intravenous use (3)
`• 10 mg/mL oral solution (3)
`
`-------------------------------CONTRAINDICATIONS------------------------------
`None (4)
`
`-----------------------WARNINGS AND PRECAUTIONS------------------------
`• Monitor patients for suicidal behavior and ideation (5.1)
`• VIMPAT may cause dizziness and ataxia (5.2)
`• Cardiac Rhythm and Conduction Abnormalities: Obtaining ECG before
`beginning and after titration to steady-state maintenance is recommended in
`patients with underlying proarrhythmic conditions or on concomitant
`medications that affect cardiac conduction; closely monitor these patients
`(5.3, 7.2)
`• VIMPAT may cause syncope (5.4)
`• VIMPAT should be gradually withdrawn to minimize the potential of
`increased seizure frequency (5.5)
`• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/
`Multi-Organ Hypersensitivity: Discontinue if no alternate etiology (5.6)
`
`------------------------------ADVERSE REACTIONS----------------------------
`• Adjunctive therapy: Most common adverse reactions in adults (≥10% and
`greater than placebo) are diplopia, headache, dizziness, nausea, and
`somnolence (6.1)
`• Monotherapy: Most common adverse reactions are similar to those seen in
`adjunctive therapy studies (6.1)
`• Pediatric patients: Adverse reactions are similar to those seen in adult
`patients (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact UCB, Inc. at
`1-844-599-2273 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
`
`-----------------------USE IN SPECIFIC POPULATIONS------------------------
`• Pregnancy: Based on animal data, may cause fetal harm (8.1)
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide
`
`Revised: 11/2021
`
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Renal Impairment
`8.7 Hepatic Impairment
`9 DRUG ABUSE AND DEPENDENCE
` 9.1 Controlled Substance
`9.2 Abuse
`9.3 Dependence
`10 OVERDOSAGE
`11 DESCRIPTION
`11.1 VIMPAT Tablets
`11.2 VIMPAT Injection
`11.3 VIMPAT Oral Solution
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 Monotherapy in Patients with Partial-Onset Seizures
`14.2 Adjunctive Therapy in Patients with Partial-Onset Seizures
`14.3 Adjunctive Therapy in Patients with Primary Generalized Tonic-
`Clonic Seizures
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16.1 How Supplied
`16.2 Storage and Handling
`17 PATIENT COUNSELING INFORMATION
`
` *
`
` Sections or subsections omitted from the full prescribing information are not
`listed.
`
`
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`VIMPAT® safely and effectively. See full prescribing information for
`VIMPAT.
`
`VIMPAT® (lacosamide) film coated tablet, for oral use, CV
`VIMPAT® (lacosamide) injection, for intravenous use, CV
`VIMPAT® (lacosamide) oral solution, CV
`Initial U.S. Approval: 2008
`
`-------------------------RECENT MAJOR CHANGES----------------------
`Indications and Usage (1.1, 1.2)
` 10/2021
`Dosage and Administration (2.1, 2.5, 2.6)
`
` 10/2021
`
`----------------------------INDICATIONS AND USAGE---------------------------
`VIMPAT is indicated for:
`• Treatment of partial-onset seizures in patients 1 month of age and older
`(1.1)
`• Adjunctive therapy in the treatment of primary generalized tonic-clonic
`seizures in patients 4 years of age and older (1.2)
`
`----------------------DOSAGE AND ADMINISTRATION-----------------------
`• Adults (17 years and older)
`o Initial dosage for monotherapy for the treatment of partial-onset seizures
`is 100 mg twice daily (2.1)
`o Initial dosage for adjunctive therapy for the treatment of partial-onset
`seizures or primary generalized tonic-clonic seizures is 50 mg twice
`daily (2.1)
`o Maximum recommended dosage for monotherapy and adjunctive therapy
`is 200 mg twice daily (2.1)
`• Pediatric Patients 1 month to less than 17 years: The recommended dosage
`is based on body weight and is administered orally twice daily (2.1)
`• Increase dosage based on clinical response and tolerability, no more
`frequently than once per week (2.1)
`• Injection: for intravenous use only when oral administration is temporarily
`not feasible; the recommended dosage is based on body weight and is
`administered two or three times daily over 15 to 60 minutes; obtaining
`ECG before initiation is recommended in certain patients (2.6, 5.3)
`• Dose adjustment is recommended for severe renal impairment (2.3, 12.3)
`• Dose adjustment is recommended for mild or moderate hepatic impairment; use
`in patients with severe hepatic impairment is not recommended (2.4, 12.3)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1 INDICATIONS AND USAGE
`1.1 Partial-Onset Seizures
`1.2 Primary Generalized Tonic-Clonic Seizures
`2 DOSAGE AND ADMINISTRATION
`2.1 Dosage Information
`2.2 Converting From a Single Antiepileptic (AED) to VIMPAT
`Monotherapy for the Treatment of Partial-Onset Seizures
`2.3 Dosage Information for Patients with Renal Impairment
`2.4 Dosage Information for Patients with Hepatic Impairment
`2.5 Administration Instructions for VIMPAT Tablets and Oral Solution
`2.6 Preparation and Administration Information for VIMPAT Injection
`2.7 Discontinuation of VIMPAT
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Suicidal Behavior and Ideation
`5.2 Dizziness and Ataxia
`5.3 Cardiac Rhythm and Conduction Abnormalities
`5.4 Syncope
`5.5 Withdrawal of Antiepileptic Drugs (AEDs)
`5.6 Drug Reaction with Eosinophilia and Systemic Symptoms
`(DRESS)/Multi-Organ Hypersensitivity
`5.7 Risks in Patients with Phenylketonuria
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Postmarketing Experience
`7 DRUG INTERACTIONS
` 7.1 Strong CYP3A4 or CYP2C9 Inhibitors
` 7.2 Concomitant Medications that Affect Cardiac Conduction
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Lactation
`
`

`

`
`
`
`FULL PRESCRIBING INFORMATION
`
`INDICATIONS AND USAGE
`
`Partial-Onset Seizures
`
` 1
`
`
`
`
`1.1
`
`VIMPAT is indicated for the treatment of partial-onset seizures in patients 1 month of age and older.
`
`
`
`1.2
`
`Primary Generalized Tonic-Clonic Seizures
`
`VIMPAT is indicated as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in
`patients 4 years of age and older.
`
`DOSAGE AND ADMINISTRATION
`
` 2
`
`
`
`
`2.1 Dosage Information
`
`The recommended dosage for monotherapy and adjunctive therapy for partial-onset seizures in patients 1 month
`of age and older and for adjunctive therapy for primary generalized tonic-clonic seizures in patients 4 years of
`age and older is included in Table 1. In pediatric patients, the recommended dosing regimen is dependent upon
`body weight. Dosage should be increased based on clinical response and tolerability, no more frequently than
`once per week. Titration increments should not exceed those shown in Table 1.
`
`Table 1: Recommended Dosages for Partial-Onset Seizures (Monotherapy or Adjunctive Therapy) in
`Patients 1 Month and Older, and for Primary Generalized Tonic-Clonic Seizures (Adjunctive Therapy)
`in Patients 4 Years of Age and Older*
`
`
`Age and Body
`Weight
`
`Adults (17 years and
`older)
`
`Initial Dosage
`
`
`Titration Regimen
`
`Maintenance Dosage
`
`Monotherapy**:
`100 mg twice daily
`(200 mg per day)
`
`Increase by 50 mg twice daily
`(100 mg per day)
`every week
`
`Monotherapy**:
`150 mg to 200 mg twice daily
`(300 mg to 400 mg per day)
`
`Adjunctive Therapy:
`50 mg twice daily
`(100 mg per day)
`
`
`Alternate Initial
`Dosage:
`
`200 mg single loading
`dose, followed 12 hours
`later by 100 mg twice
`daily
`
`Pediatric patients
`weighing 50 kg or
`more
`
`50 mg twice daily
`(100 mg per day)
`
`Increase by 50 mg twice daily
`(100 mg per day) every week
`
`Adjunctive Therapy:
`100 mg to 200 mg twice daily
`(200 mg to 400 mg per day)
`
`Monotherapy**:
`150 mg to 200 mg twice daily
`(300 mg to 400 mg per day)
`
`Adjunctive Therapy:
`100 mg to 200 mg twice daily
`(200 mg to 400 mg per day)
`
`
`
`

`

`
`
`
`
`Age and Body
`Weight
`
`Initial Dosage
`
`
`Titration Regimen
`
`Maintenance Dosage
`
`Pediatric patients
`weighing 30 kg to less
`than 50 kg
`
`1 mg/kg twice daily
`(2 mg/kg/day)
`
`
`Increase by 1 mg/kg twice
`daily (2 mg/kg/day) every
`week
`
`2 mg/kg to 4 mg/kg twice daily
`(4 mg/kg/day to 8 mg/kg/day)
`
`Pediatric patients
`weighing 11 kg to less
`than 30 kg
`
`Pediatric patients
`weighing 6 kg to less
`than 11 kg ±
`
`Pediatric patients
`weighing less than 6
`kg ±
`
`1 mg/kg twice daily
`(2 mg/kg/day)
`
`
`Increase by 1 mg/kg twice
`daily (2 mg/kg/day) every
`week
`
`3 mg/kg to 6 mg/kg twice daily
`(6 mg/kg/day to 12 mg/kg/day)
`
`Intravenous:
`
`Intravenous:
`
`Intravenous:
`
`Increase by 0.66 mg/kg three
`times daily (2 mg/kg/day)
`every week
`
`2.5 mg/kg to 5 mg/kg three times
`daily
`(7.5 mg/kg/day to 15 mg/kg/day)
`
`0.66 mg/kg three times
`daily (2 mg/kg/day)
`
`
`
`
`Oral:
`
`Oral:
`
`
`
`Oral:
`
`3.75 mg/kg to 7.5 mg/kg twice daily
`(7.5 mg/kg/day to 15 mg/kg/day)
`
`Increase by 1 mg/kg twice
`1 mg/kg twice daily
`daily (2 mg/kg/day) every
` (2 mg/kg/day)
`week
`
`*when not specified, the dosage is the same for monotherapy for partial-onset seizures and adjunctive therapy for partial-onset
`seizures or primary generalized tonic-clonic seizures. Oral and intravenous dosages are the same unless specified.
`**Monotherapy for partial-onset seizures only
`± indicated only for partial-onset seizures
`
`In adjunctive clinical trials in adult patients with partial-onset seizures, a dosage higher than 200 mg twice daily
`(400 mg per day) was not more effective and was associated with a substantially higher rate of adverse reactions
`[see Adverse Reactions (6.1) and Clinical Studies (14.2)].
`
`VIMPAT Injection Dosage
`
`VIMPAT injection may be used when oral administration is temporarily not feasible [see Dosage and
`Administration (2.6) and Warnings and Precautions (5.3)]. VIMPAT injection can be administered
`intravenously to adult and pediatric patients weighing 6 kg or more with the same dosing regimens described
`for oral dosing. For pediatric patients weighing less than 6 kg, VIMPAT injection may be initiated with a dose
`of 0.66 mg/kg three times daily (see Table 1).
`
`The clinical study experience of intravenous VIMPAT is limited to 5 days of consecutive treatment.
`
`
`
`
`
`Loading Dose in Adult Patients (17 Years and Older)
`
`VIMPAT and VIMPAT injection may be initiated in adult patients with a single loading dose of 200 mg,
`followed approximately 12 hours later by 100 mg twice daily (200 mg per day).
`
`The maintenance dose regimen should be continued for one week. VIMPAT can then be titrated as
`recommended in Table 1. The adult loading dose should be administered with medical supervision because of
`
`

`

`
`
`
`the increased incidence of CNS adverse reactions [see Adverse Reactions (6.1) and Clinical Pharmacology
`(12.3)].
`
` The use of a loading dose in pediatric patients has not been studied.
`
`2.2 Converting From a Single Antiepileptic (AED) to VIMPAT Monotherapy for the Treatment of
`Partial-Onset Seizures
`
`For patients who are already on a single AED and will convert to VIMPAT monotherapy, withdrawal of the
`concomitant AED should not occur until the therapeutic dosage of VIMPAT is achieved and has been
`administered for at least 3 days. A gradual withdrawal of the concomitant AED over at least 6 weeks is
`recommended.
`
`2.3 Dosage Information for Patients with Renal Impairment
`
`For patients with mild to moderate renal impairment, no dosage adjustment is necessary.
`For patients with severe renal impairment [creatinine clearance (CLCR) less than 30 mL/min as estimated by the
`Cockcroft-Gault equation for adults; CLCR less than 30 mL/min/1.73m2 as estimated by the Schwartz equation
`for pediatric patients] or end-stage renal disease, a reduction of 25% of the maximum dosage is recommended.
`
`In all patients with renal impairment, the dose titration should be performed with caution.
`
`Hemodialysis
`
`VIMPAT is effectively removed from plasma by hemodialysis. Following a 4-hour hemodialysis treatment,
`dosage supplementation of up to 50% should be considered.
`
`Concomitant Strong CYP3A4 or CYP2C9 Inhibitors
`
`Dose reduction may be necessary in patients with renal impairment who are taking strong inhibitors of CYP3A4
`and CYP2C9 [see Drug Interactions (7.1), Use in Specific Populations (8.6), and Clinical Pharmacology
`(12.3)].
`
`2.4 Dosage Information for Patients with Hepatic Impairment
`
`For patients with mild or moderate hepatic impairment, a reduction of 25% of the maximum dosage is
`recommended. The dose titration should be performed with caution in patients with hepatic impairment.
`VIMPAT use is not recommended in patients with severe hepatic impairment.
`
`Concomitant Strong CYP3A4 and CYP2C9 Inhibitors
`
`Dose reduction may be necessary in patients with hepatic impairment who are taking strong inhibitors of
`CYP3A4 and CYP2C9 [see Drug Interactions (7.1), Use in Specific Populations (8.7), and Clinical
`Pharmacology (12.3)].
`
`2.5 Administration Instructions for VIMPAT Tablets and Oral Solution
`
`VIMPAT tablets and oral solution may be taken with or without food.
`
`
`VIMPAT Tablets
`
`VIMPAT tablets should be swallowed whole with liquid. Do not divide VIMPAT tablets.
`
`

`

`
`
`
`
`VIMPAT Oral Solution
`
`A calibrated measuring device is recommended to measure and deliver the prescribed dose accurately. A
`household teaspoon or tablespoon is not an adequate measuring device.
`
`VIMPAT oral solution may also be administered using a nasogastric tube or gastrostomy tube.
`
`Discard any unused VIMPAT oral solution remaining after 6 months of first opening the bottle.
`
`2.6 Preparation and Administration Information for VIMPAT Injection
`
`Preparation
`
`VIMPAT injection can be administered intravenously without further dilution or may be mixed with diluents
`listed below. The diluted solution should not be stored for more than 4 hours at room temperature.
`
`Diluents:
`
`Sodium Chloride Injection 0.9% (w/v)
`Dextrose Injection 5% (w/v)
`Lactated Ringer's Injection
`
`Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
`administration, whenever solution and container permit. Product with particulate matter or discoloration should
`not be used.
`
`VIMPAT injection is for single-dose only. Any unused portion of VIMPAT injection should be discarded.
`
`
`Administration
`
`The recommended infusion duration is 30 to 60 minutes; however, infusions as rapid as 15 minutes can be
`administered in adults if required [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Infusion
`durations less than 30 minutes are generally not recommended in pediatric patients [see Adverse Reactions
`(6.1)].
`
`Intravenous infusion of VIMPAT may cause bradycardia, AV blocks, and ventricular tachyarrhythmia [see
`Warnings and Precautions (5.3)]. Obtaining an ECG before beginning VIMPAT and after VIMPAT is titrated
`to steady-state maintenance dose is recommended in patients with underlying proarrhythmic conditions or on
`concomitant medications that affect cardiac conduction [see Drug Interactions (7.2)].
`
`Storage and Stability
`
`The diluted solution should not be stored for more than 4 hours at room temperature. Any unused portion of
`VIMPAT injection should be discarded.
`
`2.7 Discontinuation of VIMPAT
`
`When discontinuing VIMPAT, a gradual withdrawal over at least 1 week is recommended [see Warnings and
`Precautions (5.5)].
`
`DOSAGE FORMS AND STRENGTHS
`
` 3
`
`
`
`VIMPAT Tablets
`
`• 50 mg: pink, oval, film-coated, debossed with "SP" on one side and "50" on the other
`
`

`

`
`
`
`
`• 100 mg: dark yellow, oval, film-coated, debossed with "SP" on one side and "100" on the other
`
`• 150 mg: salmon, oval, film-coated, debossed with "SP" on one side and "150" on the other
`
`• 200 mg: blue, oval, film-coated, debossed with "SP" on one side and "200" on the other
`
`VIMPAT Injection
`
`• 200 mg/20 mL: clear, colorless sterile solution in single-dose vials
`
`
`VIMPAT Oral Solution
`
`• 10 mg/mL: clear, colorless to yellow or yellow-brown, strawberry-flavored liquid
`
`CONTRAINDICATIONS
`
`4
`
`WARNINGS AND PRECAUTIONS
`
`Suicidal Behavior and Ideation
`
`None.
`
` 5
`
`
`
`
`5.1
`
`Antiepileptic drugs (AEDs), including VIMPAT, increase the risk of suicidal thoughts or behavior in patients
`taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for
`the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood
`or behavior.
`
`Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs
`showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk
`1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these
`trials, which had a median treatment duration of 12 weeks, the estimated incidence of suicidal behavior or
`ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated
`patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530
`patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated
`patients, but the number of events is too small to allow any conclusion about drug effect on suicide.
`
`The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting
`treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the
`analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not
`be assessed.
`
`The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The
`finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests
`that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100
`years) in the clinical trials analyzed.
`
`Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
`
`
`
`
`
`
`
`
`

`

`
`
`
`
`Table 2:
`
`Indication
`
`Risk by Indication for Antiepileptic Drugs in the Pooled Analysis
`
`Placebo Patients
`with Events
`Per 1000 Patients
`
`Drug Patients
`with Events Per
`1000 Patients
`
`Relative Risk:
`Incidence of
`Events in Drug
`Patients/Incidence in
`Placebo Patients
`
`Risk
`Difference:
`Additional Drug
`Patients with
`Events Per 1000
`Patients
`2.4
`2.9
`0.9
`1.9
`
`Epilepsy
`Psychiatric
`Other
`Total
`
`1.0
`5.7
`1.0
`2.4
`
`3.4
`8.5
`1.8
`4.3
`
`3.5
`1.5
`1.9
`1.8
`
`
`The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials
`for psychiatric or other conditions, but the absolute risk differences were similar.
`
`Anyone considering prescribing VIMPAT or any other AED must balance this risk with the risk of untreated
`illness. Epilepsy and many other illnesses for which antiepileptics are prescribed are themselves associated with
`morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and
`behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms
`in any given patient may be related to the illness being treated.
`
`5.2 Dizziness and Ataxia
`
`VIMPAT may cause dizziness and ataxia in adult and pediatric patients. In adult patients with partial-onset
`seizures taking 1 to 3 concomitant AEDs, dizziness was experienced by 25% of patients randomized to the
`recommended doses (200 to 400 mg/day) of VIMPAT (compared with 8% of placebo patients) and was the
`adverse event most frequently leading to discontinuation (3%). Ataxia was experienced by 6% of patients
`randomized to the recommended doses (200 to 400 mg/day) of VIMPAT (compared to 2% of placebo patients).
`The onset of dizziness and ataxia was most commonly observed during titration. There was a substantial
`increase in these adverse events at doses higher than 400 mg/day [see Adverse Reactions (6.1)].
`
`5.3 Cardiac Rhythm and Conduction Abnormalities
`
`PR Interval Prolongation, Atrioventricular Block, and Ventricular Tachyarrhythmia
`
`Dose-dependent prolongations in PR interval with VIMPAT have been observed in clinical studies in adult
`patients and in healthy volunteers [see Clinical Pharmacology (12.2)]. In adjunctive clinical trials in adult
`patients with partial-onset seizures, asymptomatic first-degree atrioventricular (AV) block was observed as an
`adverse reaction in 0.4% (4/944) of patients randomized to receive VIMPAT and 0% (0/364) of patients
`randomized to receive placebo. One case of profound bradycardia was observed in a patient during a 15-minute
`infusion of 150 mg VIMPAT. When VIMPAT is given with other drugs that prolong the PR interval, further PR
`prolongation is possible.
`
`In the postmarketing setting, there have been reports of cardiac arrhythmias in patients treated with VIMPAT,
`including bradycardia, AV block, and ventricular tachyarrhythmia, which have rarely resulted in asystole,
`cardiac arrest, and death. Most, although not all, cases have occurred in patients with underlying proarrhythmic
`conditions, or in those taking concomitant medications that affect cardiac conduction or prolong the PR interval.
`These events have occurred with both oral and intravenous routes of administration and at prescribed doses as
`well as in the setting of overdose [see Overdosage (10)].
`
`

`

`
`
`
`VIMPAT should be used with caution in patients with underlying proarrhythmic conditions such as known
`cardiac conduction problems (e.g., marked first-degree AV block, second-degree or higher AV block and sick
`sinus syndrome without pacemaker), severe cardiac disease (such as myocardial ischemia or heart failure, or
`structural heart disease), and cardiac sodium channelopathies (e.g., Brugada Syndrome). VIMPAT should also
`be used with caution in patients on concomitant medications that affect cardiac conduction, including sodium
`channel blockers, beta-blockers, calcium channel blockers, potassium channel blockers, and medications that
`prolong the PR interval [see Drug Interactions (7.2)]. In such patients, obtaining an ECG before beginning
`VIMPAT, and after VIMPAT is titrated to steady-state maintenance dose, is recommended. In addition, these
`patients should be closely monitored if they are administered VIMPAT through the intravenous route [see
`Adverse Reactions (6.1) and Drug Interactions (7.2)].
`
`Atrial Fibrillation and Atrial Flutter
`
`In the short-term investigational trials of VIMPAT in adult patients with partial-onset seizures there were no
`cases of atrial fibrillation or flutter. Both atrial fibrillation and atrial flutter have been reported in open label
`partial-onset seizure trials and in postmarketing experience. In adult patients with diabetic neuropathy, for
`which VIMPAT is not indicated, 0.5% of patients treated with VIMPAT experienced an adverse reaction of
`atrial fibrillation or atrial flutter, compared to 0% of placebo-treated patients. VIMPAT administration may
`predispose to atrial arrhythmias (atrial fibrillation or flutter), especially in patients with diabetic neuropathy
`and/or cardiovascular disease.
`
`
`5.4
`
`Syncope
`
`In the short-term controlled trials of VIMPAT in adult patients with partial-onset seizures with no significant
`system illnesses, there was no increase in syncope compared to placebo. In the short-term controlled trials in
`adult patients with diabetic neuropathy, for which VIMPAT is not indicated, 1.2% of patients who were treated
`with VIMPAT reported an adverse reaction of syncope or loss of consciousness, compared with 0% of placebo-
`treated patients with diabetic neuropathy. Most of the cases of syncope were observed in patients receiving
`doses above 400 mg/day. The cause of syncope was not determined in most cases. However, several were
`associated with either changes in orthostatic blood pressure, atrial flutter/fibrillation (and associated
`tachycardia), or bradycardia. Cases of syncope have also been observed in open-label clinical partial-onset
`seizure studies in adult and pediatric patients. These cases were associated with a history of risk factors for
`cardiac disease and the use of drugs that slow AV conduction.
`
`5.5 Withdrawal of Antiepileptic Drugs (AEDs)
`
`As with all AEDs, VIMPAT should be withdrawn gradually (over a minimum of 1 week) to minimize the
`potential of increased seizure frequency in patients with seizure disorders.
`
`5.6 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity
`
`Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multi-organ
`hypersensitivity, has been reported in patients taking antiepileptic drugs, including VIMPAT. Some of these
`events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash,
`lymphadenopathy and/or facial swelling, in association with other organ system involvement, such as hepatitis,
`nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection.
`Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here
`may be involved. It is important to note that early manifestations of hypersensitivity (e.g., fever,
`lymphadenopathy) may be present even though rash is not evident. If such signs or symptoms are present, the
`patient should be evaluated immediately. VIMPAT should be discontinued if an alternative etiology for the
`signs or symptoms cannot be established.
`
`

`

`
`
`
`
`5.7 Risks in Patients with Phenylketonuria
`
`Phenylalanine can be harmful in patients with phenylketonuria (PKU). VIMPAT oral solution contains
`aspartame, a source of phenylalanine. A 200 mg dose of VIMPAT oral solution (equivalent to 20 mL) contains
`0.32 mg of phenylalanine. Before prescribing VIMPAT oral solution to a patient with PKU, consider the
`combined daily amount of phenylalanine from all sources, including VIMPAT oral solution.
`
`ADVERSE REACTIONS
`
` 6
`
`
`
`
`The following serious adverse reactions are described below and elsewhere in the labeling:
`• Suicidal Behavior and Ideation [see Warnings and Precautions (5.1)]
`• Dizziness and Ataxia [see Warnings and Precautions (5.2)]
`• Cardiac Rhythm and Conduction Abnormalities [see Warnings and Precautions (5.3)]
`• Syncope [see Warnings and Precautions (5.4)]
`• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity
`Reactions [see Warnings and Precautions (5.6)]
`
`
`6.1 Clinical Trials Experience
`
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the
`clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not
`reflect the rates observed in practice.
`
`
`VIMPAT Tablet and Oral Solution in Adults
`
`In the premarketing development of adjunctive therapy for partial-onset seizures, 1327 adult patients received
`VIMPAT tablets in controlled and uncontrolled trials, of whom 1000 were treated for longer than 6 months, and
`852 for longer than 12 months. The monotherapy development program for partial-onset seizures included 425
`adult patients, 310 of whom were treated for longer than 6 months, and 254 for longer than 12 months.
`
`
`Partial-Onset Seizures
`Monotherapy Historical-Control Trial (Study 1)
`In the monotherapy trial for partial-onset seizures, 16% of patients randomized to receive VIMPAT at the
`recommended doses of 300 and 400 mg/day discontinued from the trial as a result of an adverse reaction.
`The adverse reaction most commonly (≥1% on VIMPAT) leading to discontinuation was dizziness.
`
`Adverse reactions that occurred in this study were generally similar to those that occurred in adjunctive
`placebo-controlled studies. One adverse reaction, insomnia, occurred at a rate of ≥2% and was not reported
`at a similar rate in previous studies. This adverse reaction has also been observed in postmarketing
`experience [see Adverse Reactions (6.2)]. Because this study did not include a placebo control group,
`causality could not be established.
`
`Dizziness, headache, nausea, somnolence, and fatigue all occurred at lower incidences during the AED
`Withdrawal Phase and Monotherapy Phase, compared with the Titration Phase [see Clinical Studies (14.1)].
`
`
`Adjunctive Therapy Controlled Trials (Studies 2, 3, and 4)
`In adjunctive therapy controlled clinical trials for partial-onset seizures, the rate of discontinuation as a
`result of an adverse reaction was 8% and 17% in patients randomized to receive VIMPAT at the
`recommended doses of 200 and 400 mg/day, respectively, 29% at 600 mg/day (1.5 times greater than the
`
`

`

`
`
`
`
`maximum recommended dose), and 5% in patients randomized to receive placebo. The adverse reactions
`most commonly (>1% on VIMPAT and greater than placebo) leading to discontinuation were dizziness,
`ataxia, vomiting, diplopia, nausea, vertigo, and blurred vision.
`
`Table 3 gives the incidence of adverse reactions that occurred in ≥2% of adult patients with partial-onset
`seizures in the VIMPAT total group and for which the incidence was greater than placebo.
`
`
`Table 3: Adverse Reactions Incidence in Adjunctive Therapy Pooled, Placebo-Controlled Trials in Adult
`Patients with Partial-Onset Seizures (Studies 2, 3, and 4)
`
`
`
`Placebo
`N=364
`%
`
`VIMPAT
`200 mg/day
`N=270
`%
`
`
`Adverse Reaction
`Ear and labyrinth disorder
` Vertigo
`Eye disorders
` Diplopia
` Blurred Vision
`Gastrointestinal disorders
`7
`4
` Nausea
`6
`3
` Vomiting
`3
`3
` Diarrhea
`General disorders and administration site conditions
` Fatigue
`6
`7
` Gait disturbance
`<1
`<1
` Asthenia
`1
`2
`Injury, poisoning and procedural complications
` Contusion
`3
`3
` Skin laceration
`2
`2
`Nervous system disorders
` Dizziness
` Headache
` Ataxia
` Somnolence
` Tremor
` Nystagmus
` Balance disorder
` Memory impairment
`Psychiatric disorders
` Depression
`Skin and subcutaneous disorders
`3
`1
` Pruritus
`*600 mg dose is 1.5 times greater than the maximum recommended dose.
`
`
`1
`
`2
`3
`
`8
`9
`2
`5
`4
`4
`0
`2
`
`1
`
`5
`
`6
`2
`
`16
`11
`4
`5
`4
`2
`1
`1
`
`2
`
`VIMPAT
`400 mg/day
`N=471
`%
`
`VIMPAT
`600 mg/day*
`N=203
`%
`
`VIMPAT
`Total
`N=944
`%
`
`3
`
`10
`9
`
`11
`9
`5
`
`7
`2
`2
`
`4
`3
`
`30
`14
`7
`8
`6
`5
`5
`2
`
`2
`
`2
`
`4
`
`16
`16
`
`17
`16
`4
`
`15
`4
`4
`
`2
`3
`
`53
`12
`15
`8
`12
`10
`6
`6
`
`2
`
`3
`
`4
`
`11
`8
`
`11
`9
`4
`
`9
`2
`2
`
`3
`3
`
`31
`13
`8
`7
`7
`5
`4
`2
`
`2
`
`2
`
`

`

`
`
`
`The overall adverse reaction rate was similar in male and female patients. Although there were few non-
`Caucasian patients, no differences in the incidences of adverse reactions compared to Caucasian patients were
`observed.
`
`VIMPAT Tablet and Oral Solution in Pediatric Patients
`Safety of VIMPAT was evaluated in clinical studies of pediatric patients 1 month to less than 17 years of age
`for the treatment of partial-onset seizures. Across studies in pediatric patients with partial-onset seizures, 847
`patients 1 month to less than 17 years of age received VIMPAT oral solution or tablet, of whom 596 received
`VIMPAT for at least 1 year. Adverse reactions reported in clinical studies of pediatric patients 1 month to less
`than 17 years of age were similar to those seen in adult patients.
`
`Primary Generalized Tonic-Clonic Seizures in Patients (4 Years of Age and Older)
`Adjunctive Therapy Trial (Study 5)
`
`
`In the adjunctive therapy placebo-controlled trial for primary generalized tonic-clonic seizures, adverse
`reactions that occurred in the study were generally similar to those that occurred in partial-onset seizure
`placebo-controlled studies. The most common adverse reactions (≥ 10% on VIMPAT) reported in patients
`treated with VIMPAT were dizziness (23%), somnolence (17%), headache (14%), and nausea (10%),
`compared to 7%, 14%, 10%, and 6%, respectively, of patients who received placebo. Additionally, an
`adverse reaction not previously reported of myoclonic epilepsy was reported